Thanks to the collaborative efforts of immunologists and oncologists, cancer immunotherapy and its immunologic research made clinical and scientific breakthrough in treatment of lung cancer. Here, we assembled an outstanding team of researchers including immunologist, clinical oncologists, and cancer biologist to investigate the role of tumor-infiltrating myeloid cells such as macrophages and dendritic cells (DCs), and seek a new approach for myeloid cell- mediated cancer immunotherapy. Microenvironmental milieu determines the phenotype of myeloid cells. Our lab reported that Colony Stimulating Factor 1 (CSF1), one of key mediators of microenvironment, is critical for determining the immunologic function of a DC subset. It has been well known that tumor cells secrete CSF1 to alter their microenvironment and yet, the mechanism of action is not fully elucidated. Several agents targeting CSF1 receptor (CSF1R) are being tested for cancer treatment in ongoing clinical trials. We propose a new role of tumor- produced CSF1 in altering tumor immune microenvironment toward tumor progression by producing autotaxin (ATX) which increases the number of protumoral myeloid cells such as macrophages and DCs. ATX, also known as lysophospholipase D, is secreted extracellularly and enzymatically generates lysophosphatidic acid (LPA) which is the most abundant phospholipid in body fluid. LPA is well known to stimulate cellular proliferation, migration and survival for myeloid lineage cells. The proposal is based on the PI?s two new critical discoveries on myeloid cell biology; (1) ATX is highly expressed in myeloid cells under the control of CSF1 and its receptor (CSF1R) activation, (2) ATX regulates the size of the residential population of lung myeloid cells in the CSF1R-dependent manner (CSF1R-ATX pathway). Together these findings have led to the hypothesis that tumor-produced CSF1 stimulates protumoral myeloid cells to secrete ATX in order to increase the number of protumoral macrophages and DCs. To validate the hypothesis, we propose three specific aims. The basic science arm will employ the approaches for proof-of- concept by utilizing the novel transgenic mice that have the loss or excess of the target genes. The clinical arm will exploit clinical samples from patients with lung cancer to verify the proof-of- concept. Lastly, in the translational arm, we will examine the therapeutic potentials of interfering CSF1R-ATX pathway in the mouse model of lung cancer by adopting state-of-art nano-delivery system. By using novel transgenic mice specific to CSF1R-ATX pathway, the clinical materials from patients and innovative approaches, we will interrogate the CSF1R-ATX pathway in tumor- infiltrating myeloid cells, which play a key role in tumor cell biology and could lead to the development of a new therapeutic strategy for lung cancer.